Zolpidem or N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide, with the formula as below (Formula I):
is an imidazopyridine with strong sedative actions, but only with mild anxiolytic, muscle relaxant, or anticonvulsant properties, Zolpidem acts by binding to the benzodiazepine receptor component of the GABA receptor complex, and has selective affinity for the subtype of benzodiazepine receptors prevalent in the cerebellum (BZ1- or ω1-receptors) as opposed to those more commonly found in the spinal cord (BZ2- or ω2-receptors) or in the peripheral tissues (BZ3- or ω3-receptors). Zolpidem has a rapid onset and short duration of hypnotic action and at usual doses (about 5-10 mg) decreases time to sleep onset and increases duration of sleep with little apparent effect on sleep stages (Page 1037, Martindale The Complete Drug Reference, 36th Edition, Pharmaceutical Press, Grayslake, USA, 2009). Meanwhile, zolpidem has also been reported in the treatment of Parkinson disease (Daniele A, et al. Zolpidem in Parkinson's disease. Lancet 1997; 349:1222-3), and the permanent vegetative state (Clauss R, Nel W. Drug induced arousal from the permanent vegetative state. NeuroRehabilitation 2006; 21: 23-8).
Zolpidem is rapidly absorbed from the gastrointestinal tract after oral doses, peak plasma concentrations being reached within 3 hours. Zolpidem undergoes first-pass metabolism and an absolute bioavailability of about 70% has been reported. Zolpidem has an elimination half-life of about 2.5 hours and is about 92% bound to plasma proteins. It is metabolized primarily by the cytochrome P450 isoenzyme CYP3A4 and the inactive metabolites of zolpidem are excreted in the urine and feces. Zolpidem is distributed into breast milk (Salvà P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem: therapeutic implications. Clin Pharmacokinet 1995; 29: 142-53).
Generally, zolpidem is administrated as oral tablets containing the hemitartrate salt of zolpidem, with the trade name of AMBIEM®. For short-term management of insomnia, a usual oral dose of 10 mg (5 mg for elderly) is taken about 1 hr before the bedtime. A modified-release formulation of zolpidem tartrate is also available. Zolpidem oral dosage forms are not recommended to be used as needed, especially for treating middle-of-the night awakenings, due to the next-day hangover effects (daytime drowsiness and sleepiness) when administrated 1-5 hr before waking (Hindmarch et al. Residual effects of zaleplon and zolpidem following middle of the night administration five hours to one hour before awakening. Hum Psychopharcol 2001; 16(2):159-167).
People spend approximately ⅓ of their lives sleeping, and millions of people suffer from insomnia. The average adult, for example, should have 8 hours of sleep and usually gets about 6.9 hours of sleep. In 2005, the National Sleep Foundation survey showed about 75% of all adult Americans reported one or more symptoms of insomnia, and about 33% experienced insomnia almost every night. Caffeine consumption is suggested as a significant contributor to the problem.
The problem of insomnia is addressed by several mechanisms in the current market. The mechanisms are generally directed to affecting the level of naturally-occurring neurotransmitters in a subject or stimulating/inhibiting the subject's response to certain neurotransmitters. Benzodiazepine, for example, is considered a first line treatment. Benzodiazepine (BDZ) works on the GABA receptor and improves sleep quality, but it can cause severe side-effects. Non-BDZ drugs promote sleepiness and cause less side-effects, but they can cause amnesia. Both BDZ and non-BDZ drugs carry a dependency risk. Examples include Eszopiclone (LUNESTA®), flurazepam (DALMANE®), and zolpidem (AMBIEN®). Antidepressants are also used, including amitriptyline (ELAVIL®), mirtazapine (REMERON®), nefazodone (SERZONE®), doxepin (ZONALON®), and trazodone (DESYREL®). Problems with the antidepressants include, but are not limited to, risk of use in the elderly, lack of understanding mode of action, sedation, dizziness, weight gain, and increased risk with cardiovascular disease and high blood pressure. Some over-the-counter medications have also been administered to treat insomnia, such as diphenhydramine. Problems with diphenhydramine include carry-over sedation (“hangover”) and tolerance effect. Other over-the-counter drugs that find such use include, but are not limited to, doxylamine, valerian root, and melatonin, where use is limited for at least the reasons of questionable effect and consistency. Other treatments include, for example, non-pharmacological methods of relaxation therapies, behavioral training, sleep hygiene, and stimulus control. Stimulus control (intake control) has been found to be the most effective behavioral intervention.
Several disorders have been shown to have insomnia as a co-morbid condition and/or relatively specific alterations in cerebral metabolism that may benefit from treatment with a frontal hypothermia device. These co-morbid conditions make medication treatment even more difficult, because these patients are often already on multiple other medications, some of which have sleep effects themselves. Co-morbid insomnia itself has been little studied with any form of treatment. Depression is associated with severe sleep disturbances including difficulty falling asleep, difficulty staying asleep, early morning awakening, or nonrestorative sleep. Functional neuroimaging studies have shown alterations in the normal reduction in prefrontal cortex metabolism from waking to NREM sleep. The lifetime prevalence of depression in the United States is 17.1% or currently 52 million individuals suggesting that this is a significant problem. The neurobiology of sleep problems in patients with chronic pain share significant overlaps with those of insomnia suggesting another medical disorder that may benefit from the treatment of insomnia. The most common causes of pain that disrupt sleep include back pain (cost to society estimated to exceed $100 billion each year), headaches (50% of whom sleep disturbances trigger headaches and 71% of migraine sufferers have migraines that awaken them from sleep), fibromyalgia, and arthritis (osteoarthritis, rheumatoid arthritis and autoimmune diseases such as lupus). Chronic pain prevalence estimates in the United States are 10.1% for back pain, 7.1% for pain in the legs/feet, 4.1% for pain in the arms/hands, and 3.5% for headache. Chronic regional and widespread pain, are reported by 11.0% and 3.6% of respondents, respectively. Based on US Census data, this would translate into an additional market of over 50 million individuals. 70-91% of patients with post-traumatic stress disorder (PTSD) have difficulty falling or staying asleep. Medical treatments for the sleep problems in PTSD have revolved around medication management, which have associated adverse events. Studies conducted as part of the National Comorbidity Survey (NCS) have reported the prevalence of lifetime PTSD in the United States as 7.8 percent or currently a market of over 23 million individuals.
Accordingly, and for at least the above reasons, one of skill will appreciate a method of treating insomnia and insomnia-related disorders that carry less risk of side-effects and are more predictable in efficacy.
Zolpidem pharmaceutical compositions described in the prior art (e.g., US2006/0216240, WO2008/141264, US2004/0241100, and US2007/0140981) have significant disadvantages, including decreased absorption by food, slow achievement of therapeutic blood levels, difficulties to prepare, store and applying them intranasally. Some even may induce moderate to server irritation to nasal mucosa depending on the concentration. In view of the issues existed in the prior art, there is a clear need for zolpidem compositions, which provide a substantially faster onset of action for zolpidem than existing zolpidem formulations and making it suitable for the management of insomnia characterized by difficulties with sleep initiation or managing middle-of-the-night awakenings without inducing severe side effects, for example, local irritation or next-day residual effects. There is also a need for zolpidem compositions that are easy to prepare, suitable for long-term storage and have superior intranasal applicability. The present invention provides such zolpidem compositions.